Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes
Drugs
Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes
Hillel P. Cohen 0 1 2 3 4 5
Andrew Blauvelt 0 1 2 3 4 5
Robert M. Rifkin 0 1 2 3 4 5
Silvio Danese 0 1 2 3 4 5
Sameer B. Gokhale 0 1 2 3 4 5
Gillian Woollett 0 1 2 3 4 5
Hillel P. Cohen 0 1 2 3 4 5
0 Rocky Mountain Cancer Centers , Denver, CO , USA
1 Oregon Medical Research Center , Portland, OR , USA
2 Sandoz Inc. , 100 College Road West, Princeton, NJ 08540 , USA
3 Avalere Health , Washington, DC , USA
4 Novartis Ltd. , Hyderabad , India
5 IBD Center, Humanitas Clinical and Research Hospital , Milan , Italy
Introduction To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars). Methods A systematic search was conducted using the Medline and Embase databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded. Results Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein
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medicines used in supportive care as well as those used as
therapeutic agents. The medicines contained seven
different molecular entities that were used to treat 14 diseases.
The great majority of the publications did not report
differences in immunogenicity, safety, or efficacy. The nature
and intensity of safety signals reported after switching from
reference medicines to biosimilars were the same as those
already known from continued use of the reference
medicines alone. Three large multiple switch studies with
different biosimilars did not show differences in efficacy or
safety after multiple switches between reference medicine
and biosimilar. Two publications reported a loss of efficacy
or increased dropout rates.
Conclusions While use of each biologic must be assessed
individually, these results provide reassurance to healthcare
professionals and the public that the risk of
immunogenicity-related safety concerns or diminished efficacy is
unchanged after switching from a reference biologic to a
biosimilar medicine.
Keypoints
Scientific literature (1993 up to 30 June 2017) was
reviewed to identify publications that contained
primary data on single or multiple switching from
reference biological medicines to biosimilars.
A total of 90 studies were identified involving seven
molecular entities that treated 14 disease indications,
and enrolled a total of 14,225 individuals.
The great majority of studies did not report
differences in safety, efficacy, or immunogenicity
after a single switch event compared to patients that
were not switched. Only a small number (three) of
multiple switch studies have been published to date,
but likewise no differences were detected.
Overall, the results suggest a low risk of either a
safety concern or a loss of efficacy after switching to
a biosimilar.
1 Introduction
Biological medicines (biologics) are medicines made in
living systems. Biosimilars are copies of already licensed
biologics (referred to as the reference medicine) that are
highly similar, but that are made by different sponsors
using independently-derived cell lines and
separately-developed manufacturing processes [
1, 2
]. Biosimilars can
only be approved if a manufacturer demonstrates that there
are no clinically meaningful differences in safety, efficacy,
and immunogenicity when directly compared with the
reference medicine [3].
The experience with the reference medicine, in both
preapproval clinical trials and post-approval routine clinical
practice of medicine, provides a baseline for the safety and
efficacy expected for both reference medicines and their
corresponding biosimilars. To date, no new safety or
efficacy concerns have been detected in the over 10 years and
greater than 700 million days of patient experience with
biosimilars [
4
].
Nonetheless, concerns have been raised that switching
patients from reference medicines to biosimilars, or other
structurally-related biologics, may lead to increased
immunogenicity and consequential safety problems, or
even a loss of efficacy. A review of switching studies
reported in the literature is an important first step to
confirm or deny any existing pattern that may exist related to
biologic switching. Switches occur when patients receive
medicines formally designated as biosimilars, but may also
occur after manufacturing process changes have occurred,
if the process changes lead to structural modifications or
changes in the impurit (...truncated)